Process of preparing chloramines of the steroid series



United States Pate'iitG PROCESS or PREPARING CHLORAMINES OF THE STEROID SERIES Heinrich Ruschig, Frankfurt am Main Griesheinn and Josef Schmidt-Thom, Frankfurt am MainUntefliederbach, Germany, assignors to Farbwerke Hoechst Aktiengeseiischaft vormals Meister Lucius und Bi'iinin'g, Frankfurt am Main Hochst, Germany.

No Drawing. Application June 17, 1952, Serial No. 294,055

Claims priority, applicationGei-many June 20, 195i 4 Claims. cum-397.2

The present invention relates to a process of preparing chloramines of the steroid series.

There has already been described a process of; preparing chloramines of the steroid series in'U. S.P 12,286892,' 2,108,646, and in Medizin und Chemie, volu'in'e IV, page 339, according to which steroid amines dissolved in ether are reacted with hypochlorous acid prepared according to Wohl-Goldschmidt (Berichte der Deutschen Chemischen Gesellschaft, volume 46, page 2731 (1 913)) k'lihe reaction proceeds according to the following sc eme:

on; CH3 CE;

I -H 1 NH: I Ho'o CHsC O CH3 CH3 CH3 .{I NHCI Hi0 CHaCO O The water formed during the reaction is bound byanhydrous sodium sulfate.

This method of working employed on ,a small scale gives satisfactory yields; in large scale production, however. the preparation of the anhydrous hypochlorous acid in ether is complicated and time-consuming. Afur'thr disadvantage resides in the fact that the ethereal solutions of the hydrochlorous acid decompose so thatthe solution, after standing for some hours, ,has firstto be titrated in order to determine its content of'hypochlorous acid.

Now we have found that the preparation on a large scale of chloramines of the *steroidiseries can be simplified considerably by using N-chlorosuccinimide instead of anhydrous hypochlorous acid. This finding is very surprising as, according to Ziegler (Liebigs Annalen/der Chemie, volume 551, page 80) it iskriown th'at'chlorosuccinimide is extremely slow to react as compared with bromosuccinimide.

N-chlorosuccinimide, for instance, reacts already at room temperature instantaneously with 3-acetoXy-ternorcholenyl-(5)-amine-(20) according to the following scheme:

2,697,107 Patented Dec. 14, 1954 ice .The reaction is advantageouslycarried out in indifferent organic solvents. As inditferent organic solvents there may be used for instance: benzene,.toluene, methylene chloride, 'chl0roforrn,..dioxan, and tetr ahydrofu'rane. Ether is particularly suitable as an indifferent organic solvent. When employing sparingly soluble amines, thereaction may also be carried out in suspension as the reaction products as well asthe succinimide are soluble.v The reaction is advantageously. conducted at roomtemperature, the components reacting for. the most part instantaneously. The reaction can also be carried out at lower temperatures, for IHSIHIICB. below 0;.C.;.however, the reaction time is then correspondingly longer. v.

As starting material there may .be. used: steroid amines wherein the amino group is a substituentinthe steroid system, especially in the l7-position, and also such steroid amines wherein the amino group is situated in an aliphatic radical forming a substituent in the ,l 7-position of the steroid system, "for example: f 3 acetoxy-ternorcho lenyl- (5)-ami ne-'(20), 3 hydroxY-ahdros'tene-(S)-amine-(l7), 3 acetoxy-bisnorcholanyl-amine-(22), 3 oxo-l7-aminoan'droste'iie-( i), cholesterylamine, cholesteryl methylarnine, 3-an ino-androstene-(5)-ol-(l7), and the 'like. Amino salts may also'be used as starting materials, but in this case the amine may first be liberated with the corresponding quantity of alcoholic solution of alkali hydroxide. 1

"As compared to the known method with hypochlorous acid, the process according to the present invention is particularly simple. N-chlorosuccinimide is a stablecompound which keeps for an unlimited time. The succinimide which forms duringthereaction can be recovered. Moreover, anhydrous sodium sulfate need not be applied as water .is. notiormed when theamines of the steroid series are reacted with N-chlorosuccinimide.

The'chloroairiines of thesteroid series obtained accordingto theprocess of the present inventionserve as .intermediateproductsh .They can be. converted into oxo-compounds, for example, by treatment with metal alcoholates and subsequent hydrolysis of the products. obtained... .In thiswaythere'can beobtained, ,for instance, pregnene- (.5)-'ol-(3)-one (20) from 3 -.acetoxy ternor .cholenyl- (5)-amine-(20), dehydroandrosterone from 3.-hydroxyandrostene (5) timing-(17 o xybisnorcholanaldehyde from 3-acetoXy-bisnorcholanyl ainine-(22), androstenedionefirom 3 oxo-l7.-amino-androstene-(4). V H

Th following examples serve to illustrate the invention, but they are not intended to limit it thereto.

Example 1 2 2.6fg..ojf finely powdered andsievd N-chlorosucciniiriide (99%) are added,;whil e stirring, at room temperature to a dried ethereal solution (4 litres) containing 60 g. of 3-acetoxy ternbrchol'enyl-(S)-amiiie-( 20). N-chlorosuccinimide dissolves, whereupon the solution shows a neutral reaction The solution is filtered-to remove some flakes and is then concentrated on the water bath to 1I2-1.4 liters, while succinimide crystallizes out. The mixture is filtered with suction, and the mother liquor is, under reduced pressure, concentrated to dryness leaving S-acetoXy-tern0rcholenyl-(5)-chloroamine(20) as a white crystalline magma. After treatment with metal alcoholates and subsequent hydrolysis it is converted into pregnene- (5)-ol-(3)-one-(20) (Medizin und Chemie, volume IV, page 339).

Example 2 185.8 g. of N-chlorosuccinimide (96%) are added, while stirring, at room temperature, to a solution of 480 g. of 3-acetoxy-ternorcholenyl-(5)-amine-(20) in 28 liters of absolute ether. After a short time the solution shows a neutral reaction. Stirring is continued for an additional (20) as a white crystalline magma in a quantitative yield.

The product is further treated as described in Example 1.

Example 3 2 g. of 3-oXy-androstene-(5)-amine-(17) are suspended in 150 cc. of dry ether, 2 g. of finely powdered N-chlorosuccinimide (87%) are added, and the mixture is stirred for 1 /2 hours at room temperature during which time the obtained chloramine dissolves whilst the succinimide formed remains undissolved for the most part. The mixture is filtered, half of the ether solution is distilled OE and allowed to cool. Further succinirnide crystallizes out which is also filtered off. The ether solution is concentrated to dryness leaving 3-hydroxy-androstene-(5)-chloroamine-( 17) as a white crystalline magma in a quantitative yield. Recrystallized from aqueous acetone or from ether it melts at 290 C. with decomposition. It is stable and can be stored for a long time. Further processing to dehydro-androsterone is performed by treatment with metal alcoholates and subsequent hydrolysis according to Medizin und Chemie, volume 1V, page 341 or according to U. S. Patent 2,286,892.

Example 4 13.4 g. of N-chlorosuccinimide (99%) are added, while stirring, at room temperature to a solution of 36.1 g. of 3-acetoxy-ternorcholanyl-amine-(20) in 3 liters of absolute ether. After a short time the solution shows a neutral reaction. Stirring is continued for an additional 30 minutes, the reaction solution is filtered and then concentrated on the water bath until crystallisation sets in. After cooling, the precipitated succinimide is filtered off with suction, and the filtrate is, under reduced pressure, evaporated to dryness leaving 3-acetoxy-ternorcholanyl-chloroamine-(20) as a white crystalline magma.

It can be converted into pregnanolone according to the process described in U. S. Patent 2,286,892.

Example 5 3.75 g. of 3-acetoXy-bisnorcholanyl-amine-(22) are dissolved in absolute ether, and to this solution are added, while stirring and cooling with ice, 1.34 g. of N-chlorosuccinimide (99%). The mixture is stirred for an additional 30 minutes. The ether solution is then concentrated and cooled. The succinimide that has crystallized out is filtered off, and the ether solution is evaporated to dryness. The chloryl compound of the 3-acetoxy-bis-norcholanylamine-(22) is obtained as an amorphous substance in a quantitative yield.

9 Example 6 To a solution of 2.87 g. of 3-oxo-17-amino-androstene- (4) in 1 liter of absolute ether there are added at a temperature of -5 C., while stirring vigorously, 1.34 g. of N-chlorosuccinimide. After a short time the solution shows a neutral reaction and is then concentrated. On cooling, the formed succinimide separates. After filtering, the ether solution is evaporated to dryness. 3-oXo-17- chloro-amino-androstene-(4) is obtained in a practically quantitative yield.

It can be converted into androstenedione according to the process described in U. S. Patent 2,286,892.

Example 7 3.85 g. of cholesterylamine are dissolved in ether and, while stirring, there are added 1.34 g. of N-chlorosuccinimide at room temperature. Stirring is continued for some time, the mixture is filtered, and the solution is then concentrated. On cooling, the precipitated succinimide is filtered off with suction, and the filtrate is evaporated to dryness. Cholesteryl-chloroamine is obtained in a quantitative yield.

Cholestenone can be obtained from cholesteryl-chloroamine by heating with a solution of sodium alcoholate and allowing the reaction mixture to stand after acidifying with sulfuric acid according to the process described in U. S. Patent 2,286,892.

Example 8 2.87 g. of 3-amine-androstene-(5)-ol(17) are dissolved in absolute ether and to the solution are added, while stirring, 1.34 g. of N-chlorosuccinimide. The solution is concentrated, allowed to cool, and filtered. Subsequently the filtrate is evaporated to dryness. 3-chloroaminoandrostene-(5)-ol-(17) is obtained which can be converted into testosterone by treating with metal alcoholates and subsequent hydrolysis according to the process described in Medizin und Chemie, volume 4, page 341.

Chloroform or methylene chloride can also be used as solvents instead of ether.

Example 9 4.0 g. of cholesterylmethylamine are dissolved in absolute ether and 1.35 g. of N-chlorosuccinimide are added, while stirring vigorously. The ether solution is concentrated, the succinimide precipitated on cooling is filtered off with suction, and the filtrate is evaporated to dryness. The chloryl compound of cholesteryl methylamine is obtained as colorless crystals in a quantitative yield.

The compound obtained can be converted into cholestenone by further processing it according to the process of U. S. Patent 2,286,892.

Dioxan or tetrahydrofurane can also be used as solvents instead of ether.

We claim:

1. The process of preparing amines of the steroid series chlorinated in the amino group, which comprises reacting, in an organic solvent, N-chlorosuccinimide with amines of the steroid series.

2. The process of preparing amines of the steroid series chlorinated in the amino group, which comprises reacting, in an organic solvent, N-chlorosuccinimide with amines of the steroid series, wherein the amino group is a nuclear substitutent in the steroid system.

3. The process of preparing amines of the steroid series chlorinated in the amino group, which comprises reacting, in an organic solvent, N-chlorosuccinimide with an amine of the steroid series, wherein the amino group is situated in the 17-position ot' the steroid system.

4. The process of preparing amines of the steroid series chlorinated in the amino group, which comprises reacting, in an organic solvent, N-chlorosuccinimide with amines of the steroid series, wherein the amino group is situated in an aliphatic radical forming a substituent in the 17-position of the steroid system.

References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,286,892 Bockmuhl June 16, 1942 2,531,688 Jones Nov. 28, 1950 

1. THE PROCESS OF PREPARING AMINE S OF THE STEROID SERIES CHLORINATED IN THE AMINO GROUP, WHICH COMPRISES REACTING, IN AN ORGANIC SOLVENT, N-CHLOROSUCCINIMIDE WITH AMINES OF THE STEROID SERIES. 